The present invention is generally related to substituted 4-phenyl-pyridine compounds showing activity as Neurokinin 1 Receptors (NK-1, substance P) antagonists and more particularly to the compounds, methods for their synthesis and methods of treatment of disease using these compounds.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors. The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting. In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist. The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in xe2x80x9cNeuropeptides, 32(1), 1-49, (1998)xe2x80x9d and xe2x80x9cEur. J. Pharmacol., 383(3), 297-303, (1999)xe2x80x9d.
The present invention relates to compounds of the formula 
wherein
R is hydrogen or halogen;
R1 is xe2x80x94(Cxe2x89xa1C)mR1xe2x80x2 or xe2x80x94(CRxe2x80x2xe2x95x90CRxe2x80x3)mR1xe2x80x2
wherein R1xe2x80x2 is
a) hydrogen or halogen,
b) cyano, or the following groups: 
d)xe2x80x94C(O)NRxe2x80x2Rxe2x80x3,
e)xe2x80x94C(O)O(CH2)mR5,
f)xe2x80x94C(O)R5,
g)xe2x80x94N(OH)xe2x80x94(CH2)mR5,
h)xe2x80x94NRxe2x80x2C(O)xe2x80x94(CH2)mR5,
i)xe2x80x94N[C(O)xe2x80x94Rxe2x80x2]2,
j)xe2x80x94OR6,
k)xe2x80x94(CH2)mxe2x80x94SR6, xe2x80x94(CH2)mxe2x80x94S(O)R6, or xe2x80x94(CH2)mxe2x80x94S(O)2R6,
l) aryl, unsubstituted or substituted by at least one substituent, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, xe2x80x94NRxe2x80x2Rxe2x80x3, nitro, xe2x80x94(CH2)nORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, xe2x80x94C(O)ORxe2x80x2 or xe2x80x94C(O)Rxe2x80x2,
m) is a five or six membered unsubstsituted heteroaryl group, containing one to four heteroatoms, selected from N, O or S or substituted by at least one substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, xe2x80x94NRxe2x80x2Rxe2x80x3, nitro, xe2x80x94(CH2)nORxe2x80x2, xe2x80x94C(O)ORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3 or xe2x80x94C(O)Rxe2x80x2,
n) is a five or six membered saturated or unsaturated heterocycles 
that contain one nitrogen atom or one nitrogen atom and one additional heteroatom, selected from N, O or S,
Rxe2x80x2/Rxe2x80x3 are independently from each other hydrogen, hydroxy, lower alkyl, cycloalkyl or aryl, wherein the lower alkyl, cycloalkyl or aryl group may be optionally substituted by one or more substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, xe2x80x94NRxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3, nitro, xe2x80x94(CH2)nORxe2x80x2xe2x80x3, xe2x80x94C(O)NRxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3, xe2x80x94C(O)ORxe2x80x2xe2x80x3 or xe2x80x94C(O)Rxe2x80x2xe2x80x3,
Rxe2x80x2xe2x80x3/Rxe2x80x3xe2x80x3 are independently from each other hydrogen, lower alkyl, cycloalkyl or aryl,
R5 is hydrogen, cyano, hydroxy, halogen, trifluoromethyl, xe2x80x94C(O)ORxe2x80x2, xe2x80x94OC(O)Rxe2x80x2 or aryl, unsubstituted or substituted by at least one substituent, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, xe2x80x94NRxe2x80x2Rxe2x80x3, nitro, xe2x80x94(CH2)nORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, xe2x80x94C(O)ORxe2x80x2 or xe2x80x94C(O)Rxe2x80x2, or is a five or six membered unsubstituted heteroaryl group, containing one to four heteroatoms, selected from N, or S or a substituted heteroaryl group, containing one to four heteroatoms selected from N, O or S substituted by at least one substituent, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, xe2x80x94NRxe2x80x2Rxe2x80x3, nitro, xe2x80x94(CH2)nORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, xe2x80x94C(O)ORxe2x80x2 or xe2x80x94C(O)Rxe2x80x2,
R6 is hydrogen, lower alkyl, trifluoromethyl, or aryl, or substituted lower alkyl or aryl group by at least one substituent, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, xe2x80x94NRxe2x80x2Rxe2x80x3, nitro, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)n, ORxe2x80x2, xe2x80x94C(O)ORxe2x80x2 or xe2x80x94C(O)Rxe2x80x2, or is a five or six membered aromatic heterocyclic group, containing one to four heteroatoms, selected from N, O or S and unsubstituted or substituted by at least one substituents, selected from halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, hydroxy, xe2x80x94NRxe2x80x2Rxe2x80x3, nitro, xe2x80x94(CH2)nORxe2x80x2, xe2x80x94C(O)NRxe2x80x2Rxe2x80x3, xe2x80x94C(O)ORxe2x80x2 or xe2x80x94C(O)Rxe2x80x2,
R7 is xe2x80x94C(O)xe2x80x94(CH2)mOH or an oxo group;
R2 is hydrogen, lower alkyl, lower alkoxy, halogen or CF3;
R3/R3xe2x80x2 are independently from each other hydrogen, lower alkyl or form together with the carbon atom to which they are attached a cycloalkyl group;
R4/R4xe2x80x2 are independently from each other hydrogen, halogen, CF3, lower alkyl or lower alkoxy;
R and R2 or R4 and R4xe2x80x2 may be together xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, optionally substituted by one or two substituents selected from lower alkyl, halogen or lower alkoxy;
X is xe2x80x94C(O)N(R8)xe2x80x94, (CH2)pOxe2x80x94, xe2x80x94(CH2)pN(R8)xe2x80x94, xe2x80x94N(R8)C(O)xe2x80x94 or xe2x80x94N(R8)xe2x80x94(CH2)pxe2x80x94;
wherein R8 is hydrogen or lower alkyl;
n is 1 or 2;
m is 0, 1, 2, 3 or 4;
o is 1 or 2; and
p is 1 or 2;
or a pharmaceutically acceptable acid addition salt thereof.
The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain.
Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.